The present invention relates to pharmaceutical drug delivery systems for the controlled release of absorption window active agents which: (1) have an absorption window in the gastrointestinal tract (i.e., are usually absorbed in the duodenum and/or jejunum); (2) have a locus of treatment in or proximal to the gastrointestinal tract (e.g., stomach and/or duodenum); or (3) degrade in the colon. The invention also relates to the uses of these controlled release delivery systems in the treatment of various disorders and diseases in mammals.
Conventional drug delivery systems, such as immediate release drug delivery systems, have only limited use for: (1) active agents having an absorption window in the gastrointestinal tract; (2) active agents which have a locus of treatment in or proximal to the gastrointestinal tract; and (3) active agents which degrade in the colon. Conventional sustained release dosage forms of such active agents are difficult to formulate because typical sustained release formulations will release such active agents in areas of the GI tract that do not adequately absorb such active agents. Thus, it is difficult to formulate such active agents in a controlled release formulation to obtain the benefits of the controlled release formulations, such as reducing dosing frequency and minimizing drug plasma level peaks and troughs.
Certain active agents have an absorption window in the gastrointestinal tract. The absorption of these active agents, such as, for example, baclofen, are site specific. Baclofen is primarily absorbed in the upper gastrointestinal (GI) tract. Furthermore, the extent of absorption of baclofen is substantially reduced in the lower GI tract. Absorption may be dose-dependent, being reduced with increasing doses. An improved method of administering an active agent with a limited absorption window, such as baclofen, to a patient would include the delivery of effective amounts of the drug to the upper GI tract for an extended period.
In addition, several side effects may be associated with the administration of active agents to mammals, particularly when administered as immediate release dosage forms. For example, the side effects of baclofen include nausea, vomiting, diarrhea, dizziness, daytime sedation, and less frequently, psychotic states such as depressive mood disorders. In addition, patient compliance with a dosing regimen can be suboptimal where frequent doses are required, such as the need for administering a pharmaceutical dosage form three or four times a day. A pharmaceutical dosage form that requires less frequent dosing, such as once or twice a day, would be preferable. Furthermore, a pharmaceutical dosage form capable of establishing and maintaining stable plasma levels of the active agent for a prolonged period of time may benefit patients by requiring less frequent dosing and/or by minimizing side effects.
Various other formulations for active agents having an absorption window have been described. For example, one pharmaceutical dosage form for baclofen involves adhesive tablets placed in contact with the oral mucosa to deliver the active agent across the mucous membrane. This pharmaceutical dosage form, however, exhibits various known disadvantages associated with adhesive tablets. Furthermore, the adhesive tablets deliver baclofen to a site considered suboptimal for γ-aminobutyric acid (GABA)-related agents. Other proposed formulations for active agents having an absorption window include matrix dosage forms that exhibit marked swelling and high dimensional stability in the swollen state to facilitate extended gastric residence time. In addition, an osmotic pump type dosage form for delivering an active agent with an absorption window has been proposed that provides for the continuous administration of active agent over a prolonged period of time.
Nevertheless, there remains a significant and continuing need for pharmaceutical dosage forms suitable for providing sustained release of active agents having an absorption window. In addition, there remains a need for pharmaceutical dosage forms for active agents with an absorption window that establish and maintain stable plasma levels of the active agent for a prolonged period of time to achieve less frequent dosing and to minimize side effects. These and other objectives are accomplished by the present invention.